The proposed project is a case-control study designed to investigate the role of site, gender and race in human papillomavirus (HPV) -positive head and neck squamous cell cancer (HNSCC). HPV is an established etiologic agent in a subset of HNSCCs which largely arise from the oropharynx and is an independent marker of improved prognosis. It appears to be responsible for a shifting epidemiology: oropharyngeal cancer is rapidly rising and is projected to overtake cervical cancer. Men and Whites bear the disproportionate burden of HPV-positive HNSCCs. Reasons for this unique demographic distribution are pooriy understood. Given the strong associations of HPV-HNSCC with sexual behaviors, we will explore if gender- and race- related differences in behaviors (sexual, tobacco and alcohol) may in part be responsible for these demographic pattems. We will also investigate whether gender- and racial- differences in immunologic response are driving these distinct demographic pattems. In addition, it is presently unknown how often HPV causes malignancy in non-oropharyngeal squamous cell cancers, despite the potential therapeutic implications. Therefore, the aims of this proposal are to 1) explore the relative etiologic roles of tumor HPV, tobacco, alcohol and drug use, on odds of non-oropharyngeal site head and neck squamous cell cancer, 2) determine gender differences in risk factors for HPV-HNSCC compared to age, gender, and race matched non-cancer controls and 3) evaluate differences in risk factors for oropharyngeal cancer In black and white patients compared to age, gender, and race matched non-cancer controls.